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Microscopic colitis: studies of epidemiology, clinical features and nitric oxide
Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lymphocytic colitis (LC) and collagenous colitis (CC) arc newly recognised inflammatory bowel diseases belonging to the group of microscopic colitides (MC). They are characterised clinically by chronic non-bloody and watery diarrhoea, and a macroscopically normal or near normal colonic mucosa where diagnostic histopathological abnormalities are found.

The aims of this thesis were to study the epidemiology of LC and CC in Örebro, the clinical features and outcome of treatment in a large Swedish cohort of patients with LC and the familial occurrence of MC. Further objectives were to study luminal levels of colonic nitric oxide (NO), plasma concentrations of the metabolites nitrate/nitrite and the epithelial expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in patients with MC and correlate to clinical and histopathological status.

Whereas previously thought to be rare diseases, our epidemiological study in Örebro 1993- 1998 showed that the annual incidence of LC and CC is close to the figures generally reported in Sweden in Crohn's disease. The combined rates of LC and CC are nearly as high as the incidence of ulcerative colitis. Microscopic colitis was diagnosed in 10% of all patients referred for a colonoscopy due to non-bloody diarrhoea, and in almost 20% of those older than 70 years.

The clinical features and outcome of treatment in LC were studied retrospectively in 199 Swedish patients. Diarrhoea was the predominant symptom, followed by abdominal pain and weight loss. Forty percent had at least one associated autoimmune or inflammatory disease; the most common were thyroid disorder and coeliac disease. A single attack occurred in 63% with a median disease duration of six months. In 1 0% a drug induced disease was suspected. A sudden onset of disease was noted in 25% and a non-significant peak of disease onset was seen in December-Janumy. The sudden onset, the single attack of limited duration, and the possible seasonality of the disease's onset may indicate an infectious etiology in some cases.

Corticosteroids, prednisolone as well as budesonide, were the most effective therapy in our retrospective LC study and more than 80% of the patients improved short-term. However, the relapse risk was high after withdrawal of therapy. A response rate of 50-70% was noted for loperamide, cholestyramine, metronidazole and mesalazine.

A family history of bowel disease- ulcerative colitis, Crohn's disease, CC or coeliac diseasewas reported in 12% of the 199 LC patients, and ulcerative colitis or Crohn's disease alone in 7%. We also report a familial occurrence of MC in five families, with two affected members in each family. In two families the members had different types of MC whereas in three families they all had CC.

Increased plasma levels of nitrate/nitrite and greatly enhanced levels of colonic luminal NO were found in MC patients. The NO levels were associated to the histopathological status and correlated with the clinical activity, indicating that NO is involved in the pathophysiology of MC. Expression of eN OS in the epithelium was not increased in patients with MC. An increased expression of iNOS was seen apically in the surface epithelium in MC patients, and a correlation between the staining intensity of iNOS and luminal NO levels, pointing towards the epithelial cells being the cellular source of the NO production.

Place, publisher, year, edition, pages
Linköpin: Linköping Universitet , 2004. , 37 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 830
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24731Local ID: 6982ISBN: 91-7373-800-X (print)OAI: oai:DiVA.org:liu-24731DiVA: diva2:245054
Public defence
2004-01-23, Wilandersalen, Universitetssjukhuset, Örebro, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved
List of papers
1. Microscopic colitis: a common diarrhoeal disease: an epidemiological study in Örebro, Sweden, 1993–1998
Open this publication in new window or tab >>Microscopic colitis: a common diarrhoeal disease: an epidemiological study in Örebro, Sweden, 1993–1998
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2004 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 53, no 3, 346-350 p.Article in journal (Refereed) Published
Abstract [en]

Background: Microscopic colitis, including collagenous colitis and lymphocytic colitis, mainly affects middle aged and older subjects, with a female predominance in collagenous colitis. The diseases have previously been regarded as rare. We present an epidemiological study of microscopic colitis in a well defined Swedish population.

Methods: Patients were retrospectively searched for in colonoscopy reports of those who had a colonoscopy in the period 1993–1998 for non-bloody diarrhoea. All colonic mucosal biopsies were reassessed using strict diagnostic criteria.

Results: Biopsies from 1018 patients were reassessed. Fifty one (45 female) collagenous colitis patients and 46 (31 female) lymphocytic colitis patients were diagnosed. Median age at diagnosis was 64 years in collagenous colitis and 59 years in lymphocytic colitis. The mean annual incidence of collagenous colitis was 4.9/105 inhabitants (95% confidence interval (CI) 3.6–6.2/105) and of lymphocytic colitis 4.4/105 inhabitants (95% CI 3.1–5.7/105). The annual incidence of collagenous colitis increased from 3.7/105 in 1993–1995 to 6.1/105 in 1996–1998 (difference 2.4/105 (95% CI −0.3–5.1/105)) whereas the incidence of lymphocytic colitis increased from 3.1/105 to 5.7/105 (difference 2.6/105 (95% CI 0.1–5.2/105)).

Conclusions: The annual incidences of collagenous colitis and lymphocytic colitis are higher than considered previously and are now equal to the incidence of Crohn’s disease in Sweden, and combined rates approach the incidence of ulcerative colitis. Microscopic colitis was diagnosed in 10% of all patients with non-bloody diarrhoea referred for colonoscopy and in almost 20% of those older than 70 years.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33374 (URN)10.1136/gut.2003.014431 (DOI)19389 (Local ID)19389 (Archive number)19389 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-26Bibliographically approved
2. Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients
Open this publication in new window or tab >>Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients
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2004 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 53, no 4, 536-541 p.Article in journal (Refereed) Published
Abstract [en]

Background: Lymphocytic colitis is characterised by chronic diarrhoea and specific microscopic changes in a macroscopically normal colonic mucosa. We report clinical features and treatment outcome in a large patient cohort.

Methods: Patients were searched for in 24 Swedish gastroenterology clinics. The biopsy material was reassessed using strict histopathological criteria. Clinical data were obtained from medical notes.

Results: Lymphocytic colitis was diagnosed in 199 cases. The female:male ratio was 2.4:1. Median age at diagnosis was 59 (48–70) years. The most frequent symptoms were diarrhoea (96%), abdominal pain (47%), and weight loss (41%). The course was chronic intermittent in 30% of patients, chronic continuous in 7%, and a single attack in 63%, and in these cases the disease duration was 6 (4–11) months. Seventy nine (40%) patients reported associated diseases, of which thyroid disorders, coeliac disease, and diabetes mellitus were the most common. In 34 first or second degree relatives of 24 (12%) patients, a family history of ulcerative colitis, Crohn’s disease, collagenous colitis, or coeliac disease was reported. Drug induced disease was suspected in 19 (10%) patients. A non-significant peak of disease onset was seen in December-January. More than 80% of treated patients improved on corticosteroids, including budesonide.

Conclusions: A family history of other bowel disorders is a new finding. The sudden onset and single attack of limited duration may support a possible infectious cause in some cases. Drugs may cause lymphocytic colitis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33372 (URN)10.1136/gut.2003.023440 (DOI)19387 (Local ID)19387 (Archive number)19387 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-26Bibliographically approved
3. Familial occurrence of microscopic colitis: a report on five families
Open this publication in new window or tab >>Familial occurrence of microscopic colitis: a report on five families
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2001 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 36, no 9, 959-962 p.Article in journal (Refereed) Published
Abstract [en]

Background: The etiology and pathogenesis of microscopic colitis is unknown. Whether genetic predisposition is of importance, as in many other gastrointestinal diseases, is unknown. Familial occurrence of collagenous colitis has earlier been reported only in two families.

Methods: Familial occurrence of microscopic colitis was searched for in a Swedish national microscopic colitis register.

Results: Familial occurrence of microscopic colitis was identified in five families. In all families a sister- sister relationship was found. Two sisters with collagenous colitis had been living apart in different Nordic countries for many years before developing the disease. In one pair, the smoking sister had collagenous colitis and the never smoking sister had lymphocytic colitis.

Conclusions: Considering the relative rarity of microscopic colitis, these findings indicate that a genetic predisposition may be of importance.

Keyword
collagenous colitis; familiar occurrence; genetic predisposition; lymphocytic colitis; microscopic colitis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84919 (URN)10.1080/00365520120415 (DOI)11521987 (PubMedID)
Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2017-12-07Bibliographically approved
4. Increased nitric oxide production in collagenous and lymphocytic colitis
Open this publication in new window or tab >>Increased nitric oxide production in collagenous and lymphocytic colitis
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1997 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 27, no 10, 869-871 p.Article in journal (Refereed) Published
Abstract [en]

The production of nitric oxide (NO) is increased in active ulcerative colitis and in Crohn's disease. We have studied NO production in collagenous colitis (CC) and lymphocytic colitis (LC), both of which are inflammatory bowel disorders of unknown aetiology. NO levels were measured directly in gas sampled from the colon during colonoscopy. Plasma levels of NO metabolites (nitrate/nitrite) were also measured. Luminal NO levels were more than 100 times higher in patients with CC compared with controls. In addition, plasma levels of nitrate/nitrite were increased in the patients as compared with controls. Measurements of NO directly in the colon or its oxidation products in plasma may be a helpful tool in further understanding the role of NO in the pathophysiology of CC and LC. Moreover, it is tempting to speculate that these measurements could be clinically useful in the diagnosis and therapy monitoring of these two inflammatory bowel diseases.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84920 (URN)10.1046/j.1365-2362.1997.2230757.x (DOI)
Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2017-12-07Bibliographically approved
5. Luminal nitric oxide and epithelial expression of inducible and endothelial nitric oxide synthase in collagenous and lymphocytic colitis
Open this publication in new window or tab >>Luminal nitric oxide and epithelial expression of inducible and endothelial nitric oxide synthase in collagenous and lymphocytic colitis
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2003 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 38, no 1, 66-72 p.Article in journal (Refereed) Published
Abstract [en]

Background: Colonic nitric oxide (NO) production in collagenous colitis (CC) has been studied in a small number of patients and found increased. The cellular source of NO is believed to be the colonic epithelial cells. The aim of this study was to investigate colonic NO levels in patients with CC and lymphocytic colitis (LC), to compare with the histopathological status and with the clinical activity, and to assess the epithelial expression of inducible and endothelial nitric oxide synthase (iNOS and eNOS).

Methods: We included 19 patients with CC, 8 patients with LC and 15 controls. During colonoscopy, luminal gas was sampled and NO levels were measured using the chemiluminescence technique. Mucosal biopsies were obtained for routine histopathologic examination and immunohistochemical studies of iNOS and eNOS. Clinical activity, as measured by the mean frequency of daily bowel movements during the week prior to colonoscopy, was assessed.

Results: Luminal NO levels, median (25-75 percentiles), in the patients with CC and LC were greatly increased compared to the controls, 1673 (145-8143) parts per billion (ppb) and 1838 (1065-2694) ppb versus 28 (20-46) ppb (P < 0.005, both). A positive association was seen between NO levels and histopathological status as well as clinical activity. Strong expression of iNOS was seen in the surface epithelium in 5 of 6 patients with CC and in 2 of 5 patients with LC.

Conclusions: The fact that luminal NO levels are related to histopathological status and correlate with clinical activity indicates that NO is involved in the pathophysiology of CC and LC. The epithelial cells are the most likely source of luminal NO.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33377 (URN)10.1080/00365520310000465 (DOI)12608467 (PubMedID)19392 (Local ID)19392 (Archive number)19392 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-26Bibliographically approved

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